RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Acute Myeloid Leukemia, Myelodysplastic Syndrome, CDK8/19 Inhibitor, RVU120 (SEL120), Clinical Trial, Phase Ib Read More

Inclusion Criteria:

All the following criteria must be met for a patient to be eligible for the study:

1. Written informed consent provided prior to any study-related procedure.
2. Age ≥18 years.
3. AML diagnosis according to the 2016 World Health Organisation (WHO) classification (Arber et al. 2016) with relapsed or refractory disease who have received no more than 3 prior lines of therapy and with no available therapy who have exhausted the applicable standard of care; or Myelodysplastic Syndrome (MDS) diagnosis according to the 2016 WHO classification (Arber et al. 2016) with high-risk disease per the Revised International Prognostic Scoring System and with relapsed or refractory disease, who have received no more than 3 prior lines of therapy and with no available therapy who have exhausted the applicable standard of care.
4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
5. Patients must have been off anti-cancer treatment for 2 weeks or 5 half-lives, whichever is longer. Note: Hydroxyurea is exempted if used to reduce total white blood cell (WBC) count (see below); radiation must have been completed at least 4 weeks prior to first dose of study drug.
6. Patients must have recovered from the toxic effects of previous treatments to at least Grade 1, for neurotoxicity or alopecia to Grade 2.

7. Clinical laboratory parameters as follows:

   1. Peripheral white blood cell (WBC) count, no upper limit at Screening, but must be <10x10^9/L on Day 1 prior to first dose of study drug. Note: Patients with excessive blasts may be treated with hydroxyurea until 2 days prior to first dose of study drug to reduce WBC;
   2. Platelet count >10,000/µL; Platelet transfusion prior to first dose is permitted
   3. Serum albumin ≥ 30g/L (3.0g/dL)
   4. Normal coagulation (elevated INR, prothrombin time or APTT <1.3 x ULN acceptable);
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x the upper limit of normal (ULN);
   6. Total bilirubin ≤1.5 x ULN; and
   7. Creatinine clearance ≥60 mL/min (Cockcroft-Gault formula)
   8. Urine protein ≤ 2+ (as measured by dipstick) or ≤100 mg/24 hours urine
8. Adequate cardiac function confirmed by left ventricular ejection fraction ≥40% as per echocardiography or MUGA (Multiple Gated Acquisition) scan.
9. Life expectancy of at least 12 weeks.
10. For females of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. FCBP must commit to using two medically accepted forms of effective contraception during study participation and until 6 months after the last dose of study drug. Note: Where oral contraceptives are considered, please contact the Medical Monitor. Females must also refrain from donating blood during the same time-period.
11. For males, an effective barrier method of contraception must be used during study participation until 6 months after the last dose of study drug, if the patient is sexually active with a FCBP. Males must also refrain from donating blood or sperm during the same time-period.

12. Investigator considers the patient to be suitable for participation in the clinical study by assessing that they:

    • Understand the requirements of the clinical study and can give informed consent;
    • Can comply with study medication dosing requirements and all study-related procedures and evaluations; and
    • Are not considered to be potentially unreliable and/or not cooperative.

Exclusion Criteria:

Any of the following will exclude a patient from enrolment:

1. Active central nervous system (CNS) leukemia.
2. Previous treatment with CDK8-targeted therapy.
3. Patients who have undergone major surgery within 28 days prior to first dose of study drug.
4. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug.
5. Active Grade 2-4 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD.
6. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis).
7. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) or known active positive test of /or known active diagnosis of COVID-19 viral infection.
8. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis or chronic persistent hepatitis B and/or C.
9. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RVU120 (SEL120) (e.g. active inflammatory bowel disease, ulcerative disease, malabsorption syndrome, short bowel syndrome, uncontrolled nausea, vomiting or diarrhea).
10. Ongoing drug-induced pneumonitis.
11. Concurrent participation in another investigational clinical trial.
12. Taking any medications, herbal supplements or other substances (including smoking) that are known to be strong inhibitors or inducers of CYP1A2 or that can prolong Q wave to T wave (QT) interval and/or cause torsade de pointes within less than 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of study drug. Any exception should be discussed with the Study Sponsor Medical Director.
13. Significant cardiac dysfunction defined as myocardial infarction within 12 months of first dose of study drug, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, or poorly controlled angina.

14. Currently taking drugs that are documented, in the drug package insert, to have a risk of causing prolonged QTc or torsades de pointes (TdP) within 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of study drug. Please also consult the following

    Credible Meds web page:

    https://crediblemeds.org/index.php/login/dlcheck (Appendix F). Any exception should be discussed with the Study Sponsor Medical Director

15. Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥450 ms (Bazett's formula).
16. Any other prior or current medical condition, intercurrent illness, surgical history, physical or electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g. alcohol or drug addiction) that, in the Investigator's opinion, could jeopardize patient safety or interfere with the objectives of the study.

17. Prior history of malignancies other than AML or MDS, unless the patient has been free of the disease for 5 years or more prior to Screening. Exceptions to the ≥5-year time limit include history of the following:

    1. basal cell carcinoma of the skin;
    2. non-metastatic squamous cell carcinoma of the skin;
    3. carcinoma in situ of the cervix;
    4. carcinoma in situ of the breast;
    5. carcinoma in situ of the bladder; and
    6. incidental histological finding of prostate cancer (Tumor/Node/Metastasis [TNM] stage of T1a or T1b).
18. Pregnant or breast-feeding females.